Cryo-EM reveals alternative modes of dimerization driving activation of IKK

This is the authors' abstract. We don't add key points for this paper.

The inhibitor of κB kinase (IKK) complex integrates diverse cellular inflammatory responses, and induces transcription factor NF-κB. The molecular mechanism by which IKK becomes catalytically active in response to signaling remains unclear despite structural knowledge of the individual IKK1/α, IKK2/β, and NEMO/IKKγ protein components within its hetero-oligomeric assembly. Cryo-EM of the IKK2/β homodimer bound to an associating NEMO/IKKγ protein fragment, reveals multiple conformers. Mutual exclusivity of dimeric conformers, canonical versus alternate, is reflected in and dependent upon order-to-disorder transition of the canonical 6-helical bundle dimerization interface. Correlation of this unusual structural plasticity of IKK2/β with its biochemical and cellular activities suggests mechanistic possibilities for how association with its partner scaffold protein NEMO/IKKγ and polyubiquitin chains might dictate catalytic activation of IKK through distinct IKK2/β conformers. Significance: The inhibitor of κB kinase (IKK) complex is central to inflammatory signaling via the NF-κB family transcription factors. Its activation mechanism has remained unclear. Cryo-EM analysis reveals that the constituent kinase IKK2/β adopts structurally distinct, mutually exclusive dimeric conformations controlled by an ordered-to-disordered transition at its canonical dimerization interface. Stabilization of select IKK2/β conformers by the scaffold protein NEMO in association with poly-ubiquitin chains is regulated through modular architecture and structural plasticity of distinctive kinase-associated domains, present only in kinases of this family. This unique regulatory mechanism governing catalytic activation of IKK2/β provides a conceptual framework for targeting dysregulated NF-κB signaling in human diseases.